Extensive preclinical data supports the relevance of the MAP kinase RAS/RAF/MEK/ERK signaling pathway in cancer biology and its potential as a therapeutic target in human cancers. We previously showed that inhibition of tumor MEK and ERK1/2 phosphorylation by 1st generation MEK and ERK pharmacologic inhibitors (or shRNA knockdowns) resulted in cell death in diffuse large B- cell lymphoma (DLBCL) tumor models. MCT-1, an oncogene immediately downstream of MEK/ERK is constitutively over expressed in the vast majority of primary DLBCLs (>95%), as well as in all peripheral T-cell lymphoma (100%). Previous work from our group established that phosphorylation of MCT-1 by ERK is critical for stabilization of MCT-1 protein and for its ability to promote cell proliferation. Significantly, MCT-1 has been shown by us to alter loading of mRNAs on polyribosomes (translational profile) in lymphoma cells. Although several strategies have been developed to suppress MAPK signaling, small molecule MEK inhibitors represent the most specific and effective strategy to date. AZD6244 (ARRY-142886) is a novel 2nd generation small molecule MEK antagonist. Phase I and II clinical studies studying AZD6244 have been completed in solid tumors, however, this targeted anti-MEK agent has never been tested in lymphoma. In a collaborative effort, the Gartenhaus and Evens laboratories recently published data demonstrating the significant activity of AZD6244 in DLBCL (see: Bhalla S, Evens A, et al. Blood 2011; PMID: 21628402). We showed that AZD6244 down-regulated pERK and key substrates including MCT-1, c-MYC and MCL-1. Further, AZD6244 inhibited proliferation, decreased colony formation, and induced dose-dependent apoptosis at nanomolar (clinically achievable) concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model. We have additional exciting new data showing that AZD6244 downregulates pERK and induces death in T-cell lymphoma. Based on these pre-clinical findings, we have developed an investigator-initiated phase II trial to study the novel small-molecule MEK inhibitor, AZD6244, for patients with relapsed/refractory DLBCL. This trial was vetted and approved by CTEP; CTEP will supply and distribute drug. Furthermore, we will collaborate with the University of Chicago N01 Phase II consortium for study coordination and patient accrual. The central hypothesis of this multi-PI team science translational proposal is that interruption of the MAP kinase signaling pathway with a novel MEK inhibitor alone, and/or combined rationally with other novel targeted agents (i.e., NF8B inhibitor, dual PI3K/AKT inhibitor, mTOR inhibitor), will effectively repress the lymphoma phenotype pre-clinically in B-cell and T-cell NHL cells, in vivo SCID xenografts, and tumor graft models. Further, this will represent a new therapeutic paradigm for the treatment of lymphoma. In addition, the proposed research will investigate the molecular characterization of genetic networks through the interrogation of translational profiles, which will fundamentally advance our understanding of the biology of lymphomagenesis.